rs1555316704

Positions:

• chr14-36663072-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001372076.1(PAX9):​c.180C>A​(p.Tyr60Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAX9 NM_001372076.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.06

Genes affected

PAX9 (HGNC:8623): (paired box 9) This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. Mice lacking this gene exhibit impaired development of organs, musculature and the skeleton, including absent and abnormally developed teeth, and neonatal lethality. Mutations in the human gene are associated with selective tooth agenesis-3. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-36663072-C-A is Pathogenic according to our data. Variant chr14-36663072-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 526772.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-36663072-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX9	NM_001372076.1	c.180C>A	p.Tyr60Ter	stop_gained	2/4	ENST00000361487.7
PAX9	NM_006194.4	c.180C>A	p.Tyr60Ter	stop_gained	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX9	ENST00000361487.7	c.180C>A	p.Tyr60Ter	stop_gained	2/4	1	NM_001372076.1	P1
PAX9	ENST00000402703.6	c.180C>A	p.Tyr60Ter	stop_gained	3/5	5		P1
PAX9	ENST00000555639.2	c.180C>A	p.Tyr60Ter	stop_gained	3/3	5
PAX9	ENST00000554201.1	n.499C>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Partial congenital absence of teeth Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2021

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PAX9 are known to be pathogenic (PMID: 14607846, 16236760, 16479262). This variant has been reported in an individual with isolated hypodontia (PMID: 22581971). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr60*) in the PAX9 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.96
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555316704; hg19: chr14-37132277;